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Stem cell factor induces HIF-1alpha at normoxia in hematopoietic cells.

Author:
  • Malin Pedersen
  • Tobias Löfstedt
  • Jianmin Sun
  • Linda Holmquist Mengelbier
  • Sven Påhlman
  • Lars Rönnstrand
Publishing year: 2008
Language: English
Pages: 98-103
Publication/Series: Biochemical and Biophysical Research Communications
Volume: 98
Issue: 103
Document type: Journal article
Publisher: Elsevier

Abstract english

Signaling by the receptor for stem cell factor (SCF), c-Kit, is of major importance for hematopoiesis, melanogenesis and reproduction, and the biological responses are commonly proliferation and cell survival. Thus, constitutive activation due to c-Kit mutations is involved in the pathogenesis of several forms of cancer, e.g. leukemias, gastrointestinal stromal tumors and testicular tumors. Tumor survival requires oxygen supply through induced neovascularization, a process largely mediated by the vascular endothelial growth factor (VEGF), a prominent target of the transcription factors hypoxia-inducible factor-1 (HIF-1) and HIF-2. Using Affymetrix microarrays we have identified genes that are upregulated following SCF stimulation. Interestingly, many of the genes induced were found to be related to a hypoxic response. These findings were corroborated by our observation that SCF stimulation of the hematopoietic cell lines M-07e induces HIF-1alpha and HIF-2alpha protein accumulation at normoxia. In addition, SCF-induced HIF-1alpha was transcriptionally active, and transcribed HIF-1 target genes such as VEGF, BNIP3, GLUT1 and DEC1, an effect that could be reversed by siRNA against HIF-1alpha. We also show that SCF-induced accumulation of HIF-1alpha is dependent on both the PI-3-kinase and Ras/MEK/Erk pathways. Our data suggest a novel mechanism of SCF/c-Kit signaling in angiogenesis and tumor progression.

Keywords

  • Biological Sciences
  • Receptor
  • tyrosine kinase
  • Hypoxia
  • HIF-1 alpha
  • Affymetrix
  • Stem cell factor
  • c-Kit

Other

Published
  • ISSN: 1090-2104
Sven Påhlman
E-mail: sven [dot] pahlman [at] med [dot] lu [dot] se

Professor

Division of Translational Cancer Research

+46 46 222 64 21

MV406 312K1

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